Over the last decade, the incidence of cerebral palsy (CP) of perinatal origin has not been decreasing and has even increased in some Western countries. The costs to society are huge, from the loss of potential productive members of society and the direct burden on the individual, family, and social institutions that last the entire life. Thus CP has one of the very highest indices of burden of disease, and yet there has been no progress in developing ways of preventing CP. There is no therapy on the horizon that might help to prevent CP developing after hypoxia-ischemia. The major problems limiting progress in this key area are the lack of clinically relevant animal models for CP, lack of sufficient resources devoted to this problem, and a lack of a systematic approach to tackle the problem, all of which are addressed in this proposal. We will use the rabbit model of CP that develops after acute placental insufficiency at preterm gestation, based on the clinical paradigm of abruption placenta. This perinatal model is the first to reliably lead to CP, and so it allows us to rigorously test whether putative therapies can prevent the motor deficits of CP in animals. In addition, we will use a second, non-rodent animal model of brain injury related to another paradigm, umbilical cord occlusion, in fetal sheep. This model allows detailed fetal surveillance, to evaluate potential side-effects and, critically, allows us to confirm that potentially therapies are protective in a second, clinically-relevant large animal model. We also propose to form a study group that will utilize these robust animal models to study in utero hypoxia-ischemia (H-I) in the preterm fetus. This study group will use an algorithm to develop new therapies based on specific, clinically reproducible milestones. We will first prioritize the eight most promising therapeutic candidates for evaluation using well defined criteria. The first Aim will test the most promising drug candidates in a preterm rabbit model mimicking abruption placenta for reducing motor deficits analogous to a Phase II clinical trial. The effect on perinatal deaths and other locomotor deficits will also be determined in addition to safety to the mother. A futility design will be used to select drugs to go to the next Aim. The second Aim will take the most promising candidates identified by the first Aim and will test them in the rabbit model as in a Phase III clinical trial. The third aim will test the best candidates developed from the second aim for safety in fetal sheep and efficacy in a preterm sheep model of umbilical cord occlusion. The fetal sheep studies thus will provide essential safety data, such as the no observed adverse effect levels and supportive outcome data that cannot be ethically obtained in humans. The eventual aim of this R-21 proposal is to develop a U01 proposal to develop the promising therapies to consideration for FDA approval for preventive treatment in a mother at risk for acute placental insufficiency. The proposed studies will thus provide the framework for the systematic development of much-needed therapies for CP and thus expedite the clinical application of these therapies,